title: Mutant huntingtin gene-dose impacts on aggregate deposition, DARPP32 expression and neuroinflammation in HdhQ150 mice.
abstract: Huntington's disease (HD) is an autosomal dominant, progressive and fatal neurological disorder caused by an expansion of CAG repeats in exon-1 of the huntingtin gene. The encoded poly-glutamine stretch renders mutant huntingtin prone to aggregation. HdhQ150 mice genocopy a pathogenic repeat (∼150 CAGs) in the endogenous mouse huntingtin gene and model predominantly pre-manifest HD. Treating early is likely important to prevent or delay HD, and HdhQ150 mice may be useful to assess therapeutic strategies targeting pre-manifest HD. This requires appropriate markers and here we demonstrate, that pre-symptomatic HdhQ150 mice show several dramatic mutant huntingtin gene-dose dependent pathological changes including: (i) an increase of neuronal intra-nuclear inclusions (NIIs) in brain, (ii) an increase of extra-nuclear aggregates in dentate gyrus, (iii) a decrease of DARPP32 protein and (iv) an increase in glial markers of neuroinflammation, which curiously did not correlate with local neuronal mutant huntingtin inclusion-burden. HdhQ150 mice developed NIIs also in all retinal neuron cell-types, demonstrating that retinal NIIs are not specific to human exon-1 R6 HD mouse models. Taken together, the striking and robust mutant huntingtin gene-dose related changes in aggregate-load, DARPP32 levels and glial activation markers should greatly facilitate future testing of therapeutic strategies in the HdhQ150 HD mouse model.
authors.affiliation: Novartis Institutes for BioMedical Research, Neuroscience, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Douglas
authors.initials: D
authors.lastname: Young
authors.forename: Franziska
authors.initials: F
authors.lastname: Mayer
authors.forename: Nella
authors.initials: N
authors.lastname: Vidotto
authors.forename: Tatjana
authors.initials: T
authors.lastname: Schweizer
authors.forename: Ramon
authors.initials: R
authors.lastname: Berth
authors.forename: Dorothee
authors.initials: D
authors.lastname: Abramowski
authors.forename: Derya R
authors.initials: DR
authors.lastname: Shimshek
authors.forename: P Herman
authors.initials: PH
authors.lastname: van der Putten
authors.forename: Peter
authors.initials: P
authors.lastname: Schmid
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D018628:Gene Dosage / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D007150:Immunohistochemistry; D045586:Intranuclear Inclusion Bodies / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D009841:Oligonucleotides / Q000235:genetics; D012160:Retina / Q000473:pathology; D018709:Statistics, Nonparametric
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D009841:Oligonucleotides; C497929:Ppp1r1b protein, mouse